Wenqiang Song

United States Department of Veterans Affairs, Бедфорд, Massachusetts, United States

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Publications (6)39.66 Total impact

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    ABSTRACT: Mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase that regulates a diverse array of cellular processes including cell growth, survival, metabolism, and cytoskeleton dynamics. mTOR functions in two distinct complexes, mTORC1 and mTORC2, whose activities and substrate specificities are regulated by complex specific co-factors, including Raptor and Rictor, respectively. Little is known regarding the relative contribution of mTORC1 versus mTORC2 in vascular endothelial cells. Using mouse models of Raptor or Rictor gene targeting, we discovered that Rictor ablation inhibited VEGF-induced endothelial cell proliferation and assembly in vitro and angiogenesis in vivo, whereas loss of Raptor had only a modest effect on endothelial cells (EC). Mechanistically, loss of Rictor reduced the phosphorylation of AKT, PKCα, and NDRG1, without affecting the mTORC1 pathway. In contrast, loss of Raptor increased phosphorylation of AKT, despite inhibiting phosphorylation of S6K1, a direct target of mTORC1. Reconstitution of Rictor-null cells with Myr-AKT rescued vascular assembly in Rictor-deficient endothelial cells, whereas PKCα rescued proliferation defects. Further, tumor neovascularization in vivo were significantly decreased upon EC-specific Rictor deletion in mice. These data indicate that mTORC2 is a critical signaling node required for VEGF-mediated angiogenesis through regulation of AKT and PKCα in vascular endothelial cells. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Molecular and Cellular Biology 01/2015; 35(7). DOI:10.1128/MCB.00306-14 · 4.78 Impact Factor
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    ABSTRACT: Angiogenic remodeling during embryonic development and in adult tissue homeostasis is orchestrated by cooperative signaling between several distinct molecular pathways, which are often exploited by tumors. Indeed, tumors upregulate pro-angiogenic molecules while simultaneously suppressing angiostatic pathways in order to recruit blood vessels for growth, survival, and metastatic spread. Understanding how cancers exploit pro- and anti-angiogenic signals is a key step in developing new, molecularly targeted anti-angiogenic therapies. While EphA2, a receptor tyrosine kinase (RTK), is required for vascular endothelial growth factor (VEGF)-induced angiogenesis, the mechanism through which these pathways intersect remains unclear. Slit2 expression is elevated in EphA2-deficient endothelium, and here it is reported that inhibiting Slit activity rescues VEGF-induced angiogenesis in cell culture and in vivo, as well as VEGFdependent tumor angiogenesis, in EphA2-deficient endothelial cells and animals.Moreover, blocking Slit activity or Slit2 expression in EphA2-deficient endothelial cells restores VEGF-induced activation of Src and Rac, both of which are required for VEGFmediated angiogenesis. These data suggest that EphA2 suppression of Slit2 expression and Slit angiostatic activity enables VEGF-induced angiogenesis in vitro and in vivo, providing a plausible mechanism for impaired endothelial responses to VEGF in the absence of EphA2 function. Implications: Modulation of angiostatic factor Slit2 by EphA2 receptor regulates endothelial responses to VEGF-mediated angiogenesis and tumor neovascularization. Copyright © 2014, American Association for Cancer Research.
    Molecular Cancer Research 12/2014; 13(3). DOI:10.1158/1541-7786.MCR-14-0142 · 4.38 Impact Factor
  • Jin Chen · Wenqiang Song · Katherine Amato
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    ABSTRACT: Eph receptor tyrosine kinases (RTKs) and their ligands, ephrins, play critical roles in development, tissue homeostasis, and cancer. Because Eph receptors are expressed in most adult stem cell niches and in many types of cancers, it has been long suspected that this family of RTKs may also regulate the function of cancer stem-like cells (CSCs). This review will focus on recent studies to elucidate the contribution of Eph/ephrin molecules in CSC self-renewal and tumorigenicity, as well as describe efforts to target these molecules in cancer. Because CSCs are often resistant to therapeutic intervention and have been shown to depend on Eph RTKs for self-renewal, targeting Eph receptors may hold promise for the treatment of drug-resistant cancers.
    Cytokine & Growth Factor Reviews 05/2014; 26(1). DOI:10.1016/j.cytogfr.2014.05.001 · 5.36 Impact Factor
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    ABSTRACT: Recent genome-wide analyses in human lung cancer revealed that EPHA2 receptor tyrosine kinase is overexpressed in non-small cell lung cancer (NSCLC), and high levels of EPHA2 correlate with poor clinical outcome. However, the mechanistic basis for EPHA2-mediated tumor promotion in lung cancer remains poorly understood. Here we show that the JNK/c-JUN signaling mediates EPHA2-dependent tumor cell proliferation and motility. A screen of phospho-kinase arrays revealed a decrease in phospho-c-JUN levels in EPHA2 knockdown cells. Knockdown of EPHA2 inhibited p-JNK and p-c-JUN levels in approximately 50% of NSCLC lines tested. Treatment of parental cells with SP600125, a JNK inhibitor, recapitulated defects in EPHA2-deficient tumor cells; whereas constitutively activated JNK mutants were sufficient to rescue phenotypes. Knockdown of EPHA2 also inhibited tumor formation and progression in xenograft animal models in vivo. Furthermore, we investigated the role of EPHA2 in cancer stem-like cells. RNAi-mediated depletion of EPHA2 in multiple NSCLC lines decreased the ALDH positive cancer stem-like population and tumor spheroid formation in suspension. Depletion of EPHA2 in sorted ALDH positive populations markedly inhibited tumorigenicity in nude mice. Furthermore, analysis of a human lung cancer tissue microarray revealed a significant, positive association between EPHA2 and ALDH expression, indicating an important role for EPHA2 in human lung cancer stem-like cells. Collectively, these studies revealed a critical role of JNK signaling in EPHA2-dependent lung cancer cell proliferation and motility and a role for EPHA2 in cancer stem-like cell function, providing evidence for EPHA2 as a potential therapeutic target in NSCLC.
    Cancer Research 03/2014; 74(9). DOI:10.1158/0008-5472.CAN-13-2136 · 9.33 Impact Factor
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    ABSTRACT: VAPB (VAMP- associated protein B) is an ER protein that regulates multiple biological functions. Although aberrant expression of VAPB is associated with breast cancer, its function in tumor cells is poorly understood. In this report, we provide evidence that VAPB regulates breast tumor cell proliferation and AKT activation. VAPB protein expression is elevated in primary and metastatic tumor specimens, and VAPB mRNA expression levels correlated negatively with patient survival in two large breast tumor datasets. Overexpression of VAPB in mammary epithelial cells increased cell growth, whereas VAPB knockdown in tumor cells inhibited cell proliferation in vitro and suppressed tumor growth in orthotopic mammary gland allografts. The growth regulation of mammary tumor cells controlled by VAPB appears to be mediated, at least in part, by modulation of AKT activity. Overexpression of VAPB in MCF10A-HER2 cells enhances phosphorylation of AKT. In contrast, knockdown of VAPB in MMTV-Neu tumor cells inhibited pAKT levels. Pharmacological inhibition of AKT significantly reduced three-dimensional spheroid growth induced by VAPB. Collectively, the genetic, functional and mechanistic analyses suggest a role of VAPB in tumor promotion in human breast cancer.
    PLoS ONE 10/2012; 7(10):e46281. DOI:10.1371/journal.pone.0046281 · 3.23 Impact Factor
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    ABSTRACT: Cancer genome sequencing efforts recently identified EPHA3, which encodes the EPHA3 receptor tyrosine kinase, as one of the most frequently mutated genes in lung cancer. Although receptor tyrosine kinase mutations often drive oncogenic conversion and tumorigenesis, the oncogenic potential of the EPHA3 mutations in lung cancer remains unknown. We used immunoprecipitation, western blotting, and kinase assays to determine the activity and signaling of mutant EPHA3 receptors. A mutation-associated gene signature was generated from one large dataset, mapped to another training dataset with survival information, and tested in a third independent dataset. EPHA3 expression levels were determined by quantitative reverse transcription-polymerase chain reaction in paired normal-tumor clinical specimens and by immunohistochemistry in human lung cancer tissue microarrays. We assessed tumor growth in vivo using A549 and H1299 human lung carcinoma cell xenografts in mice (n = 7-8 mice per group). Tumor cell proliferation was measured by bromodeoxyuridine incorporation and apoptosis by multiple assays. All P values are from two-sided tests. At least two cancer-associated EPHA3 somatic mutations functioned as dominant inhibitors of the normal (wild type) EPHA3 protein. An EPHA3 mutation-associated gene signature that was associated with poor patient survival was identified. Moreover, EPHA3 gene copy numbers and/or expression levels were decreased in tumors from large cohorts of patients with lung cancer (eg, the gene was deleted in 157 of 371 [42%] primary lung adenocarcinomas). Reexpression of wild-type EPHA3 in human lung cancer lines increased apoptosis by suppression of AKT activation in vitro and inhibited the growth of tumor xenografts (eg, for H1299 cells, mean tumor volume with wild-type EPHA3 = 437.4 mm(3) vs control = 774.7 mm(3), P < .001). Tumor-suppressive effects of wild-type EPHA3 could be overridden in trans by dominant negative EPHA3 somatic mutations discovered in patients with lung cancer. Cancer-associated EPHA3 mutations attenuate the tumor-suppressive effects of normal EPHA3 in lung cancer.
    Journal of the National Cancer Institute 07/2012; 104(15):1182-97. DOI:10.1093/jnci/djs297 · 12.58 Impact Factor

Publication Stats

31 Citations
39.66 Total Impact Points


  • 2014
    • United States Department of Veterans Affairs
      Бедфорд, Massachusetts, United States
  • 2012–2014
    • Vanderbilt University
      • Department of Medicine
      Нашвилл, Michigan, United States